Heart failure & cardiomyopathies
Alternative Splicing of TPM1 Mediated by SRPK3 Drives Cardiac Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction
Authors' conclusion
AS of TPM1 exon 9a is a critical pathogenic mechanism in myofilament disorder and diastolic dysfunction in HFpEF, which is dependent on the upstream splicing kinase SRPK3.
Study context
- Population
- Patients with heart failure with preserved ejection fraction (HFpEF), HFpEF mouse models and human pluripotent stem cell-derived cardiomyocytes
Main finding
As reported in the abstract
- Unique myofilament disorders in HFpEF; TPM1b isoform (skipping exon 9a through alternative splicing (AS)) upregulated in HFpEF patients and mouse models
- TPM1b (without exon 9a) overexpression exacerbated HFpEF phenotypes in mice and human pluripotent stem cell-derived cardiomyocytes
- Splicing kinase SRPK3 mediates AS of TPM1 exon 9a
- SRPK3 overexpression induced myofiber disarray and diastolic dysfunction; SRPK3 knockdown ameliorated them
- TPM1 containing exon 9a partially rescued diastolic dysfunction under SRPK3 overexpression
- Inactivating SRPK3 alleviated diastolic dysfunction in HFpEF mouse model (preventive intervention)
Original publication
Alternative Splicing of TPM1 Mediated by SRPK3 Drives Cardiac Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction. Circulation. Published 9 June 2026. doi:10.
Summarised from the published abstract; every number is checked against it